PROJECT SUMMARY/ABSTRACT It has become increasingly appreciated that lymphocytes within non-lymphoid tissues exhibit unique effector programs that extend beyond their roles in anti-pathogen and anti-tumor immunity. Such non-immune functions, including the regulation of metabolic homeostasis and tissue repair, highlight the diversity of immunological signals that can be elaborated in a tissue-specific manner to modify physiological and developmental parameters within a given niche. To achieve these diverse regulatory roles, tissue-localized leukocytes interact with specialized non-lymphoid cells that define the organ?s function, triggering niche-specific effector programs in response to perturbations within the tissue microenvironment. In support of this mechanism, a recently described population of lung regulatory T (Treg) cells were shown to play a pronounced tissue-protective role during the early stages of acute lung injury caused by influenza virus infection in mice. Through their production of the epidermal growth factor receptor (EGFR) ligand, amphiregulin, these Treg cells support epithelial barrier regeneration and preserve lung function. Although these findings uncovered an important and previously unknown role for Treg cell?derived amphiregulin, the mechanistic details of how amphiregulin influences lung repair remained undetermined. Preliminary studies indicate that in response to lung injury caused by other damaging stimuli, infiltrating leukocyte populations other than regulatory T cells produce amphiregulin. Further inspection has suggested that amphiregulin-producing leukocytes may guide alveolar epithelial regeneration by interacting with specific lung mesenchymal and epithelial stem/progenitor cell populations that orchestrate discrete steps of the repair process. To this end, the major goals of this proposal are to 1) characterize interactions between amphiregulin-producing lung leukocytes and resident mesenchymal and epithelial stem/progenitor cells, 2) identify the molecular basis of these interactions and define their relative significance for restoring normal lung function, and 3) determine how these cellular interactions are influenced by the severity or type of damaging stimuli. Successful completion of this project will broaden our understanding of the role of tissue-specific immune responses in directing tissue regeneration and support the development of future strategies that seek to stimulate these processes to treat lung disease and restore normal organ homeostasis.